RBCC Red Blood Cell Collection

CD59 (MIC11, MIN1, MIN2, MIN3, MSK21) [Confidence: high (present in two of the MS resources)]
CD59 glycoprotein (1F5 antigen; 20 kDa homologous restriction factor; HRF-20; HRF20; MAC-inhibitory protein; MAC-IP; MEM43 antigen; Membrane attack complex inhibition factor; MACIF; Membrane inhibitor of reactive lysis; MIRL; Protectin; CD59; Flags: Precursor)

hRBCD IPI00011302
IPI00011302 CD59 glycoprotein precursor CD59 glycoprotein precursor membrane n/a n/a 1 1 1 1 1 1 n/a n/a 1 1 n/a 1 n/a n/a 1 1 n/a n/a Attached to the membrane by a GPI-anchor. n/a found at its expected molecular weight found at molecular weight

UniProt P13987
ID CD59_HUMAN Reviewed; 128 AA.
AC P13987;
DT 01-JAN-1990, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-JAN-1990, sequence version 1.
DT 22-JAN-2014, entry version 160.
DE RecName: Full=CD59 glycoprotein;
DE AltName: Full=1F5 antigen;
DE AltName: Full=20 kDa homologous restriction factor;
DE Short=HRF-20;
DE Short=HRF20;
DE AltName: Full=MAC-inhibitory protein;
DE Short=MAC-IP;
DE AltName: Full=MEM43 antigen;
DE AltName: Full=Membrane attack complex inhibition factor;
DE Short=MACIF;
DE AltName: Full=Membrane inhibitor of reactive lysis;
DE Short=MIRL;
DE AltName: Full=Protectin;
DE AltName: CD_antigen=CD59;
DE Flags: Precursor;
GN Name=CD59; Synonyms=MIC11, MIN1, MIN2, MIN3, MSK21;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=T-cell;
RX PubMed=2475570; DOI=10.1084/jem.170.3.637;
RA Davies A., Simmons D.L., Hale G., Harrison R.A., Tighe H.,
RA Lachmann P.J., Waldmann H.;
RT "CD59, an LY-6-like protein expressed in human lymphoid cells,
RT regulates the action of the complement membrane attack complex on
RT homologous cells.";
RL J. Exp. Med. 170:637-654(1989).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=1689664; DOI=10.1002/eji.1830200113;
RA Philbrick W.M., Palfree R.G.E., Roger G.E., Maher S.E., Bridgett M.M.,
RA Sirlin S., Bothwell A.L.M.;
RT "The CD59 antigen is a structural homologue of murine Ly-6 antigens
RT but lacks interferon inducibility.";
RL Eur. J. Immunol. 20:87-92(1990).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=2475111; DOI=10.1016/0006-291X(89)90852-8;
RA Okada H., Nagami Y., Takahashi K., Okada N., Hideshima T.,
RA Takizawa H., Kondo J.;
RT "20 KDa homologous restriction factor of complement resembles T cell
RT activating protein.";
RL Biochem. Biophys. Res. Commun. 162:1553-1559(1989).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=2606909;
RA Sugita Y., Tobe T., Oda E., Tomita M., Yasukawa K., Yamaji N.,
RA Takemoto T., Furuichi K., Takayama M., Yano S.;
RT "Molecular cloning and characterization of MACIF, an inhibitor of
RT membrane channel formation of complement.";
RL J. Biochem. 106:555-557(1989).
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=1692709; DOI=10.1089/dna.1990.9.213;
RA Sawada R., Ohashi K., Anaguchi H., Okazaki H., Hattori M., Minato N.,
RA Naruto M.;
RT "Isolation and expression of the full-length cDNA encoding CD59
RT antigen of human lymphocytes.";
RL DNA Cell Biol. 9:213-220(1990).
RN [6]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=1381503; DOI=10.1073/pnas.89.17.7876;
RA Petranka J.G., Fleenor D.E., Sykes K., Kaufman R.E., Rosse W.F.;
RT "Structure of the CD59-encoding gene: further evidence of a
RT relationship to murine lymphocyte antigen Ly-6 protein.";
RL Proc. Natl. Acad. Sci. U.S.A. 89:7876-7879(1992).
RN [7]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC TISSUE=Blood;
RX PubMed=1383553; DOI=10.1016/0022-2836(92)90239-G;
RA Tone M., Walsh L.A., Waldmann H.;
RT "Gene structure of human CD59 and demonstration that discrete mRNAs
RT are generated by alternative polyadenylation.";
RL J. Mol. Biol. 227:971-976(1992).
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA Phelan M., Farmer A.;
RT "Cloning of human full-length CDSs in BD Creator(TM) system donor
RT vector.";
RL Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases.
RN [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Colon;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [10]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 27-128.
RX PubMed=2476718; DOI=10.1093/nar/17.16.6728;
RA Sawada R., Ohashi K., Okano K., Hattori M., Minato N., Naruto M.;
RT "Complementary DNA sequence and deduced peptide sequence for CD59/MEM-
RT 43 antigen, the human homologue of murine lymphocyte antigen Ly-6C.";
RL Nucleic Acids Res. 17:6728-6728(1989).
RN [11]
RP PROTEIN SEQUENCE, MASS SPECTROMETRY, GLYCOSYLATION AT ASN-43, AND
RP STRUCTURE OF CARBOHYDRATES.
RX PubMed=8670172;
RA Meri S., Lehto T., Sutton C.W., Tyynelaa J., Baumann M.;
RT "Structural composition and functional characterization of soluble
RT CD59: heterogeneity of the oligosaccharide and glycophosphoinositol
RT (GPI) anchor revealed by laser-desorption mass spectrometric
RT analysis.";
RL Biochem. J. 316:923-935(1996).
RN [12]
RP GPI-ANCHOR AT ASN-102, AND DISULFIDE BONDS.
RX PubMed=8276756;
RA Sugita Y., Nakano Y., Oda E., Noda K., Tobe T., Miura N.H., Tomita M.;
RT "Determination of carboxyl-terminal residue and disulfide bonds of
RT MACIF (CD59), a glycosyl-phosphatidylinositol-anchored membrane
RT protein.";
RL J. Biochem. 114:473-477(1993).
RN [13]
RP INTERACTION WITH C8 AND C9.
RX PubMed=1377690;
RA Ninomiya H., Sims P.J.;
RT "The human complement regulatory protein CD59 binds to the alpha-chain
RT of C8 and to the ''b'' domain of C9.";
RL J. Biol. Chem. 267:13675-13680(1992).
RN [14]
RP IDENTIFICATION OF COMPLEMENT INHIBITORY DOMAIN.
RX PubMed=9235986; DOI=10.1021/bi970832i;
RA Yu J., Dong S., Rushmere N.K., Morgan B.P., Abagyan R., Tomlinson S.;
RT "Mapping the regions of the complement inhibitor CD59 responsible for
RT its species selective activity.";
RL Biochemistry 36:9423-9428(1997).
RN [15]
RP MUTAGENESIS.
RX PubMed=9053451; DOI=10.1084/jem.185.3.507;
RA Bodian D.L., Davis S.J., Morgan B.P., Rushmere N.K.;
RT "Mutational analysis of the active site and antibody epitopes of the
RT complement-inhibitory glycoprotein, CD59.";
RL J. Exp. Med. 185:507-516(1997).
RN [16]
RP STRUCTURE OF CARBOHYDRATES, STRUCTURE OF THE GPI-ANCHOR, AND PROTEIN
RP SEQUENCE OF N-TERMINUS.
RX PubMed=9054419; DOI=10.1074/jbc.272.11.7229;
RA Rudd P.M., Morgan B.P., Wormald M.R., Harvey D.J., van den Berg C.W.,
RA Davis S.J., Ferguson M.A., Dwek R.A.;
RT "The glycosylation of the complement regulatory protein, human
RT erythrocyte CD59.";
RL J. Biol. Chem. 272:7229-7244(1997).
RN [17]
RP INHIBITION BY GLYCATION, GLYCATION AT LYS-66 AND HIS-69, AND
RP MUTAGENESIS OF LYS-66 AND HIS-69.
RX PubMed=10805801; DOI=10.1073/pnas.97.10.5450;
RA Acosta J., Hettinga J., Flueckiger R., Krumrei N., Goldfine A.,
RA Angarita L., Halperin J.;
RT "Molecular basis for a link between complement and the vascular
RT complications of diabetes.";
RL Proc. Natl. Acad. Sci. U.S.A. 97:5450-5455(2000).
RN [18]
RP GPI-ANCHOR [LARGE SCALE ANALYSIS], AND MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=14517339; DOI=10.1074/mcp.M300079-MCP200;
RA Elortza F., Nuehse T.S., Foster L.J., Stensballe A., Peck S.C.,
RA Jensen O.N.;
RT "Proteomic analysis of glycosylphosphatidylinositol-anchored membrane
RT proteins.";
RL Mol. Cell. Proteomics 2:1261-1270(2003).
RN [19]
RP GPI-ANCHOR [LARGE SCALE ANALYSIS], AND MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=16602701; DOI=10.1021/pr050419u;
RA Elortza F., Mohammed S., Bunkenborg J., Foster L.J., Nuehse T.S.,
RA Brodbeck U., Peck S.C., Jensen O.N.;
RT "Modification-specific proteomics of plasma membrane proteins:
RT identification and characterization of glycosylphosphatidylinositol-
RT anchored proteins released upon phospholipase D treatment.";
RL J. Proteome Res. 5:935-943(2006).
RN [20]
RP GPI-ANCHOR AT ASN-102, AND MASS SPECTROMETRY.
RX PubMed=17566972; DOI=10.1002/pmic.200700068;
RA Omaetxebarria M.J., Elortza F., Rodriguez-Suarez E., Aloria K.,
RA Arizmendi J.M., Jensen O.N., Matthiesen R.;
RT "Computational approach for identification and characterization of
RT GPI-anchored peptides in proteomics experiments.";
RL Proteomics 7:1951-1960(2007).
RN [21]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-43, AND MASS SPECTROMETRY.
RC TISSUE=Milk;
RX PubMed=18780401; DOI=10.1002/pmic.200701057;
RA Picariello G., Ferranti P., Mamone G., Roepstorff P., Addeo F.;
RT "Identification of N-linked glycoproteins in human milk by hydrophilic
RT interaction liquid chromatography and mass spectrometry.";
RL Proteomics 8:3833-3847(2008).
RN [22]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [23]
RP STRUCTURE BY NMR OF 26-95.
RX PubMed=7512825; DOI=10.1021/bi00181a006;
RA Kieffer B., Driscoll P.C., Campbell I.D., Willis A.C.,
RA van der Merwe P.A., Davis S.J.;
RT "Three-dimensional solution structure of the extracellular region of
RT the complement regulatory protein CD59, a new cell-surface protein
RT domain related to snake venom neurotoxins.";
RL Biochemistry 33:4471-4482(1994).
RN [24]
RP STRUCTURE BY NMR OF 26-102.
RC TISSUE=Urine;
RX PubMed=7520819; DOI=10.1016/S0969-2126(00)00020-4;
RA Fletcher C.M., Harrison R.A., Lachmann P.J., Neuhaus D.;
RT "Structure of a soluble, glycosylated form of the human complement
RT regulatory protein CD59.";
RL Structure 2:185-199(1994).
RN [25]
RP INVOLVEMENT IN HACD59.
RX PubMed=1382994; DOI=10.1002/eji.1830221029;
RA Motoyama N., Okada N., Yamashina M., Okada H.;
RT "Paroxysmal nocturnal hemoglobinuria due to hereditary nucleotide
RT deletion in the HRF20 (CD59) gene.";
RL Eur. J. Immunol. 22:2669-2673(1992).
RN [26]
RP VARIANT HACD59 TYR-89.
RX PubMed=23149847; DOI=10.1182/blood-2012-07-441857;
RA Nevo Y., Ben-Zeev B., Tabib A., Straussberg R., Anikster Y.,
RA Shorer Z., Fattal-Valevski A., Ta-Shma A., Aharoni S., Rabie M.,
RA Zenvirt S., Goldshmidt H., Fellig Y., Shaag A., Mevorach D.,
RA Elpeleg O.;
RT "CD59 deficiency is associated with chronic hemolysis and childhood
RT relapsing immune-mediated polyneuropathy.";
RL Blood 121:129-135(2013).
CC -!- FUNCTION: Potent inhibitor of the complement membrane attack
CC complex (MAC) action. Acts by binding to the C8 and/or C9
CC complements of the assembling MAC, thereby preventing
CC incorporation of the multiple copies of C9 required for complete
CC formation of the osmolytic pore. This inhibitor appears to be
CC species-specific. Involved in signal transduction for T-cell
CC activation complexed to a protein tyrosine kinase.
CC -!- FUNCTION: The soluble form from urine retains its specific
CC complement binding activity, but exhibits greatly reduced ability
CC to inhibit MAC assembly on cell membranes.
CC -!- SUBUNIT: Interacts with T-cell surface antigen CD2.
CC -!- INTERACTION:
CC Q778I9:C (xeno); NbExp=4; IntAct=EBI-297972, EBI-8716052;
CC O35587:TMED10 (xeno); NbExp=5; IntAct=EBI-297972, EBI-4405327;
CC Q15363:TMED2; NbExp=4; IntAct=EBI-297972, EBI-998485;
CC -!- SUBCELLULAR LOCATION: Cell membrane; Lipid-anchor, GPI-anchor.
CC Secreted. Note=Soluble form found in a number of tissues.
CC -!- PTM: N- and O-glycosylated. The N-glycosylation mainly consists of
CC a family of biantennary complex-type structures with and without
CC lactosamine extensions and outer arm fucose residues. Also
CC significant amounts of triantennary complexes (22%). Variable
CC sialylation also present in the Asn-43 oligosaccharide. The
CC predominant O-glycans are mono-sialylated forms of the
CC disaccharide, Gal-beta-1,3GalNAc, and their sites of attachment
CC are probably on Thr-76 and Thr-77. The GPI-anchor of soluble
CC urinary CD59 has no inositol-associated phospholipid, but is
CC composed of seven different GPI-anchor variants of one or more
CC monosaccharide units. Major variants contain sialic acid, mannose
CC and glucosamine. Sialic acid linked to an N-acetylhexosamine-
CC galactose arm is present in two variants.
CC -!- PTM: Glycated. Glycation is found in diabetic subjects, but only
CC at minimal levels in nondiabetic subjects. Glycated CD59 lacks
CC MAC-inhibitory function and confers to vascular complications of
CC diabetes.
CC -!- DISEASE: Hemolytic anemia, CD59-mediated, with or without
CC polyneuropathy (HACD59) [MIM:612300]: An autosomal recessive
CC disorder characterized by infantile onset of chronic hemolysis and
CC a relapsing-remitting polyneuropathy, often exacerbated by
CC infection, and manifested as hypotonia, limb muscle weakness, and
CC hyporeflexia. Note=The disease is caused by mutations affecting
CC the gene represented in this entry.
CC -!- SIMILARITY: Contains 1 UPAR/Ly6 domain.
CC -!- WEB RESOURCE: Name=CD59base; Note=CD59 mutation db;
CC URL="http://bioinf.uta.fi/CD59base/";
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology
CC and Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/CD59ID985ch11p13.html";
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DR EMBL; M27909; AAA60543.1; -; mRNA.
DR EMBL; M95708; AAA60957.1; -; mRNA.
DR EMBL; X16447; CAA34467.1; -; mRNA.
DR EMBL; X17198; CAA35059.1; -; mRNA.
DR EMBL; M34671; AAA51952.1; -; mRNA.
DR EMBL; M84345; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; M84349; AAA88793.1; -; Genomic_DNA.
DR EMBL; M84346; AAA88793.1; JOINED; Genomic_DNA.
DR EMBL; M84348; AAA88793.1; JOINED; Genomic_DNA.
DR EMBL; Z14113; CAA78486.1; -; Genomic_DNA.
DR EMBL; Z14114; CAA78486.1; JOINED; Genomic_DNA.
DR EMBL; Z14115; CAA78486.1; JOINED; Genomic_DNA.
DR EMBL; BT007104; AAP35768.1; -; mRNA.
DR EMBL; BC001506; AAH01506.1; -; mRNA.
DR PIR; A46252; RWHU59.
DR RefSeq; NP_000602.1; NM_000611.5.
DR RefSeq; NP_001120695.1; NM_001127223.1.
DR RefSeq; NP_001120697.1; NM_001127225.1.
DR RefSeq; NP_001120698.1; NM_001127226.1.
DR RefSeq; NP_001120699.1; NM_001127227.1.
DR RefSeq; NP_976074.1; NM_203329.2.
DR RefSeq; NP_976075.1; NM_203330.2.
DR RefSeq; NP_976076.1; NM_203331.2.
DR UniGene; Hs.278573; -.
DR UniGene; Hs.709466; -.
DR UniGene; Hs.710641; -.
DR PDB; 1CDQ; NMR; -; A=26-102.
DR PDB; 1CDR; NMR; -; A=26-102.
DR PDB; 1CDS; NMR; -; A=26-102.
DR PDB; 1ERG; NMR; -; A=26-95.
DR PDB; 1ERH; NMR; -; A=26-95.
DR PDB; 2J8B; X-ray; 1.15 A; A=26-103.
DR PDB; 2OFS; X-ray; 2.12 A; A=26-99.
DR PDB; 2UWR; X-ray; 1.34 A; A=26-102.
DR PDB; 2UX2; X-ray; 1.80 A; A/B/C=26-102.
DR PDB; 4BIK; X-ray; 3.49 A; B/D=26-102.
DR PDBsum; 1CDQ; -.
DR PDBsum; 1CDR; -.
DR PDBsum; 1CDS; -.
DR PDBsum; 1ERG; -.
DR PDBsum; 1ERH; -.
DR PDBsum; 2J8B; -.
DR PDBsum; 2OFS; -.
DR PDBsum; 2UWR; -.
DR PDBsum; 2UX2; -.
DR PDBsum; 4BIK; -.
DR ProteinModelPortal; P13987; -.
DR SMR; P13987; 26-102.
DR IntAct; P13987; 10.
DR MINT; MINT-5000502; -.
DR STRING; 9606.ENSP00000340210; -.
DR PhosphoSite; P13987; -.
DR UniCarbKB; P13987; -.
DR DMDM; 116021; -.
DR PaxDb; P13987; -.
DR PeptideAtlas; P13987; -.
DR PRIDE; P13987; -.
DR DNASU; 966; -.
DR Ensembl; ENST00000351554; ENSP00000340210; ENSG00000085063.
DR Ensembl; ENST00000395850; ENSP00000379191; ENSG00000085063.
DR Ensembl; ENST00000415002; ENSP00000404822; ENSG00000085063.
DR Ensembl; ENST00000426650; ENSP00000402425; ENSG00000085063.
DR Ensembl; ENST00000437761; ENSP00000410182; ENSG00000085063.
DR Ensembl; ENST00000445143; ENSP00000403511; ENSG00000085063.
DR Ensembl; ENST00000525763; ENSP00000435179; ENSG00000085063.
DR Ensembl; ENST00000527577; ENSP00000432942; ENSG00000085063.
DR Ensembl; ENST00000528700; ENSP00000434617; ENSG00000085063.
DR GeneID; 966; -.
DR KEGG; hsa:966; -.
DR UCSC; uc001mus.4; human.
DR CTD; 966; -.
DR GeneCards; GC11M033721; -.
DR H-InvDB; HIX0171358; -.
DR HGNC; HGNC:1689; CD59.
DR HPA; CAB001448; -.
DR HPA; HPA026494; -.
DR MIM; 107271; gene.
DR MIM; 612300; phenotype.
DR neXtProt; NX_P13987; -.
DR Orphanet; 169464; Primary CD59 deficiency.
DR PharmGKB; PA26228; -.
DR eggNOG; NOG83475; -.
DR HOGENOM; HOG000232180; -.
DR HOVERGEN; HBG005284; -.
DR InParanoid; P13987; -.
DR KO; K04008; -.
DR OMA; GHSLTCY; -.
DR PhylomeDB; P13987; -.
DR Reactome; REACT_6900; Immune System.
DR ChiTaRS; CD59; human.
DR EvolutionaryTrace; P13987; -.
DR GeneWiki; CD59; -.
DR GenomeRNAi; 966; -.
DR NextBio; 4034; -.
DR PRO; PR:P13987; -.
DR ArrayExpress; P13987; -.
DR Bgee; P13987; -.
DR CleanEx; HS_CD59; -.
DR Genevestigator; P13987; -.
DR GO; GO:0031362; C:anchored to external side of plasma membrane; IDA:MGI.
DR GO; GO:0043218; C:compact myelin; IEA:Ensembl.
DR GO; GO:0005576; C:extracellular region; IBA:RefGenome.
DR GO; GO:0005615; C:extracellular space; IEA:Ensembl.
DR GO; GO:0042383; C:sarcolemma; IEA:Ensembl.
DR GO; GO:0001848; F:complement binding; IBA:RefGenome.
DR GO; GO:0007596; P:blood coagulation; TAS:ProtInc.
DR GO; GO:0001775; P:cell activation; IBA:RefGenome.
DR GO; GO:0007166; P:cell surface receptor signaling pathway; TAS:ProtInc.
DR GO; GO:0045087; P:innate immune response; TAS:Reactome.
DR GO; GO:0001971; P:negative regulation of activation of membrane attack complex; IEA:Ensembl.
DR GO; GO:0043066; P:negative regulation of apoptotic process; IEA:Ensembl.
DR GO; GO:0042102; P:positive regulation of T cell proliferation; IEA:Ensembl.
DR GO; GO:0030449; P:regulation of complement activation; TAS:Reactome.
DR InterPro; IPR018363; CD59_antigen_CS.
DR InterPro; IPR027101; CD59_glyco.
DR InterPro; IPR016054; LY6_UPA_recep-like.
DR InterPro; IPR001526; LY6_UPAR.
DR PANTHER; PTHR10036:SF0; PTHR10036:SF0; 1.
DR Pfam; PF00021; UPAR_LY6; 1.
DR SMART; SM00134; LU; 1.
DR PROSITE; PS00983; LY6_UPAR; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Cell membrane; Complete proteome;
KW Direct protein sequencing; Disease mutation; Disulfide bond;
KW Glycation; Glycoprotein; GPI-anchor; Hereditary hemolytic anemia;
KW Lipoprotein; Membrane; Reference proteome; Secreted; Signal.
FT SIGNAL 1 25
FT CHAIN 26 102 CD59 glycoprotein.
FT /FTId=PRO_0000036108.
FT PROPEP 103 128 Removed in mature form.
FT /FTId=PRO_0000036109.
FT DOMAIN 26 108 UPAR/Ly6.
FT LIPID 102 102 GPI-anchor amidated asparagine.
FT CARBOHYD 43 43 N-linked (GlcNAc...).
FT CARBOHYD 66 66 N-linked (Glc) (glycation).
FT CARBOHYD 69 69 N-linked (Glc) (glycation).
FT CARBOHYD 76 76 O-linked (GalNAc...) (Probable).
FT CARBOHYD 77 77 O-linked (GalNAc...) (Probable).
FT DISULFID 28 51
FT DISULFID 31 38
FT DISULFID 44 64
FT DISULFID 70 88
FT DISULFID 89 94
FT VARIANT 89 89 C -> Y (in HACD59).
FT /FTId=VAR_070124.
FT MUTAGEN 29 29 Y->R: No loss of function.
FT MUTAGEN 33 33 N->R,Q: No loss of function.
FT MUTAGEN 37 37 D->R: No loss of function.
FT MUTAGEN 48 48 F->R: Some loss of function. Some lysis.
FT MUTAGEN 49 49 D->R: Loss of function. Lysis.
FT MUTAGEN 58 58 L->E: No loss of function.
FT MUTAGEN 63 63 K->E: No loss of function.
FT MUTAGEN 65 65 W->E: Complete loss of function. Lysis.
FT MUTAGEN 66 66 K->D: No loss of function.
FT MUTAGEN 66 66 K->Q: Loss of glycation mediated
FT inactivation.
FT MUTAGEN 67 67 F->K: No loss of function.
FT MUTAGEN 69 69 H->Q: Loss of glycation mediated
FT inactivation.
FT MUTAGEN 72 72 F->E: Almost complete loss of function.
FT Lysis.
FT MUTAGEN 78 78 R->E: Loss of function. Lysis.
FT MUTAGEN 79 79 L->D: No loss of function.
FT MUTAGEN 81 81 E->R: Almost complete loss of function.
FT Lysis.
FT MUTAGEN 82 82 N->K: No loss of function.
FT MUTAGEN 87 87 Y->R: No loss of function.
FT STRAND 27 29
FT STRAND 32 34
FT STRAND 41 43
FT STRAND 50 56
FT STRAND 59 65
FT HELIX 67 69
FT HELIX 72 79
FT STRAND 85 89
FT STRAND 91 93
FT HELIX 97 99
SQ SEQUENCE 128 AA; 14177 MW; 2F0D29CBE3C28505 CRC64;
MGIQGGSVLF GLLLVLAVFC HSGHSLQCYN CPNPTADCKT AVNCSSDFDA CLITKAGLQV
YNKCWKFEHC NFNDVTTRLR ENELTYYCCK KDLCNFNEQL ENGGTSLSEK TVLLLVTPFL
AAAWSLHP
//

MIM 107271
*RECORD*
*FIELD* NO
107271
*FIELD* TI
*107271 CD59 ANTIGEN; CD59
;;PROTECTIN;;
HUMAN LEUKOCYTE ANTIGEN MIC11; MIC11;;
SURFACE ANTIGEN RECOGNIZED BY MONOCLONAL ANTIBODY 16.3A5
read more*FIELD* TX

CLONING

Okada et al. (1989) described a novel membrane inhibitor of the membrane
attack complexes (MACs). A 20-kD protein, its function is the same as
that of HRF (homologous restriction factor), which has a molecular mass
of 65 kD. Therefore, they termed the new protein HRF20. HRF20 was also
found to be identical to membrane attack complex inhibitory factor
(MACIF) and CD59 (Davies et al., 1989); the sequences of cDNA encoding
the 3 were essentially identical. By means of flow cytometric analysis,
HRF20 was found to be expressed on most leukocytes and erythrocytes,
indicating that it may have a role in preventing complement attack in
the circulation.

By searching for genes in a region of chromosome 11 associated with WAGR
syndrome (194072), Gawin et al. (1999) identified and cloned CD59, which
they designated clone 44686. Northern blot analysis detected variable
expression of a 6-kb transcript in all human tissues examined.

GENE FUNCTION

The CD59 antigen recognized by monoclonal antibody MEM-43 is an 18- to
25-kD glycoprotein expressed on all human peripheral blood leukocytes,
erythrocytes, and several human cell lines. A close relationship to Ly6
of the mouse has been demonstrated. Antigens encoded by both Ly6 and
CD59 genes are important to T-cell and NK-cell function. CD59 is also
known as protectin. Its function is to restrict lysis of human
erythrocytes and leukocytes by homologous complement. By directly
incorporating protectin into membranes of heterologous cells, Meri et
al. (1990) found that protectin does not prevent perforin-mediated
killing (see 170280), whereas complement killing is effectively
restricted. Thus, cell-mediated killing is unaffected by protectin. Meri
et al. (1990) described the functional characteristics of protectin.
Much attention has been focused on the Ly6 proteins because they may be
involved in lymphocyte activation, and expression of some of them occurs
at critical times in the differentiation of lymphocytes.

Walsh et al. (1992) reviewed information on CD59, which they
characterized as a multifunctional molecule with a role particularly in
inhibition of formation of membrane attack complex. They raised the
possibility that Ly6 is not a homolog and that the true MAC-inhibiting
murine homolog of CD59 had yet to be found.

Rother et al. (1994) demonstrated that retroviral transduction with a
recombinant transmembrane form of CD59 of mouse L cells deficient in GPI
anchoring resulted in surface expression of the CD59 protein and
resistance of these cells to human complement-mediated membrane damage.
Furthermore, a GPI anchoring-deficient complement-sensitive B-cell line
derived from a PNH patient was successfully transduced with the
particular form of recombinant CD59, resulting in surface expression of
the protein. These cells were protected against classic
complement-mediated membrane damage by human serum. The findings
suggested that retroviral gene therapy with this molecule could provide
a treatment for patients with paroxysmal nocturnal hemoglobinuria (PNH;
300818).

Mao et al. (1996) suggested that the RIGE gene (601384) is the closest
human homolog of the murine Ly6 gene family.

Activated terminal complement proteins C5b (120900) to C9 (120940) form
the MAC pore. Insertion of the MAC into endothelial cell membranes
causes the release of growth factors that stimulate tissue growth and
proliferation. The complement regulatory membrane protein CD59 restricts
MAC formation. Because increased cell proliferation characterizes the
major chronic vascular complications of diabetes, and because increased
glucose levels in diabetes cause protein glycation and impairment of
protein function, Acosta et al. (2000) investigated whether glycation
could inhibit CD59. Glycation-inactivation of CD59 would cause increased
MAC deposition and MAC-stimulated cell proliferation. They reported that
(1) human CD59 is glycated in vivo; (2) glycated human CD59 loses its
MAC-inhibitory function; and (3) inactivation of CD59 increases
MAC-induced growth factor release from endothelial cells. They
demonstrated by site-directed mutagenesis that residues lys41 and his44
form a preferential glycation motif in human CD59. The presence of this
glycation motif in human CD59, but not in CD59 of other species, may
help explain the distinct propensity of humans to develop vascular
proliferative complications of diabetes.

The placenta is an immunologically privileged site. Using DNA
microarrays to compare gene expression patterns, Sood et al. (2006)
found that 3 regulators of complement, CD55 (125240), CD59, and membrane
cofactor protein (MCP; 120920), are expressed at higher levels in normal
placental villus sections compared with other normal human tissues.
Within the placenta, CD55 and CD59 are expressed at greatest levels in
amnion, followed by chorion and villus sections, whereas MCP is
expressed at higher levels only in villus sections. These inhibitors of
complement are expressed on syncytiotrophoblasts, the specialized
placental cells lining the villi that are in direct contact with
maternal blood. The amnion compared with chorion is remarkably
nonimmunogenic, and the immune properties of the amnion are intriguing
because it is not in direct contact with maternal cells. Sood et al.
(2006) suggested that the amnion may secrete the complement inhibitors
themselves or in the form of protected exosomes into the amniotic fluid
or the neighboring maternofetal junction.

Morais da Silva et al. (2002) showed that the newt ortholog of CD59,
Prod1, is involved in determining the proximodistal identity of
blastemal cells during limb regeneration. Human CD59 shares 23% amino
acid identity with newt Prod1 and 34% identity with mouse Cd59. All 3
proteins contain a conserved CD59/Ly6 family motif (CCxxxxCN), and 8 of
the 10 cysteines conserved in mouse and human CD59 are found in newt
Prod1. Like CD59, Prod1 attaches to the cell surface through a
glycosylphosphatidylinositol (GPI) anchor that is cleaved by
phosphatidylinositol-specific phospholipase C (see 604114).

Kumar et al. (2007) found that in the adult salamander, limb
regeneration is dependent upon the surface protein Prod1 as a critical
determinant of proximodistal identity. The anterior gradient protein
family member newt AG, whose human homolog is AG2 (606358), is a
secreted ligand for Prod1 and a growth factor for cultured newt
blastemal cells. Newt AG is sequentially expressed after amputation in
the regenerating nerve and the wound epidermis--the key tissues of the
stem cell niche--and its expression in both locations is abrogated by
denervation. The local expression of newt AG after electroporation is
sufficient to rescue a denervated blastema and regenerate the distal
structures. Kumar et al. (2007) concluded that their analysis brought
together the positional identity of the blastema and the classical nerve
dependence of limb regeneration.

GENE STRUCTURE

Petranka et al. (1992) demonstrated that the CD59 gene contains 4 exons
spanning 20 kb. The untranslated first exon is preceded by a G+C-rich
promoter region that lacks a consensus TATA or CAAT motif. The second
exon encodes the hydrophobic leader sequence of the protein, and the
third exon encodes the N-terminal portion of the mature protein. The
fourth exon encodes the remainder of the mature protein, including the
hydrophobic sequence necessary for GPI anchor attachment. They found
that the structure of the CD59 gene is similar to that encoding Ly6.
Similarity in gene structure suggests that the 2 proteins belong to a
superfamily of proteins that may also include the urokinase plasminogen
activator receptor (173391).

Tone et al. (1992) reported that the CD59 gene is more than 27 kb long
and comprises one 5-prime untranslated exon and 3 coding exons. Northern
blot analysis using 6 different probes located in the 3-prime region of
the gene showed that more than 4 different CD59 mRNA molecules are
generated by alternative polyadenylation. Three of these polyadenylation
sites were predicted from previously published cDNA sequences.

MAPPING

Forsberg et al. (1989) used indirect immunofluorescence and
immunoblotting with MEM-43 antibody to demonstrate expression of CD59 in
Chinese hamster-human cell hybrids. CD59 was found to segregate with
hybrids containing part of the short arm of human chromosome 11 but not
with hybrids containing the long arm. They specifically assigned the
gene to 11p14-p13. Heckl-Ostreicher et al. (1993) used chromosomal in
situ hybridization and pulsed field gel electrophoresis to map the CD59
gene to 11p13, distal to the breakpoint of acute T-cell leukemia (LMO2;
180385) and proximal to the Wilms tumor gene (WT1; 607102). Ly6 is on
mouse chromosome 15 (LeClair et al., 1987). Indeed, the Ly6 multigene
family is clustered in a region closely linked to the Sis (190040) and
Myc (190080) protooncogenes (Huppi et al., 1988). Kamiura et al. (1992)
used the combined techniques of field-inversion gel electrophoresis
(FIGE), phage and cosmid genomic library screening, and 2-dimensional
DNA electrophoresis to construct a physical map of the entire Ly6
complex. The map spanned approximately 1,600 kb. Bickmore et al. (1993)
assigned the CD59 gene to 11p13 by study of somatic cell hybrids and by
pulsed field gel electrophoresis, as well as by the fact that the gene
is often deleted in WAGR individuals. This region of chromosome 11 shows
homology of synteny with mouse chromosome 2. This suggested that CD59 is
not a homolog of the mouse Ly-6 gene on mouse chromosome 15, but rather
is a related gene.

Holt et al. (2000) cloned the mouse CD59 homolog and mapped the gene by
radiation hybrid analysis to chromosome 2 in a region showing conserved
synteny with human 11p13.

MOLECULAR GENETICS

Motoyama et al. (1992) identified a single-nucleotide deletion
(107271.0001) in the CD59 gene in a patient with CD59-mediated hemolytic
anemia (HACD59; 612300) manifest as paroxysmal nocturnal hemoglobinuria.

In 5 patients from 4 unrelated families of North African Jewish descent
with CD59-mediated hemolytic anemia and immune-mediated polyneuropathy
(612300), Nevo et al. (2013) identified a homozygous mutation in the
CD59 gene (C89Y; 107271.0002). The mutation was initially found by
whole-exome sequencing in 2 affected sibs, segregated with the disorder
in all families, and was not found in the dbSNP or the Exome Variant
Server database. Haplotype analysis indicated a founder effect. The
patients presented in infancy with a relapsing-remitting polyneuropathy,
often exacerbated by infection, and characterized by hypotonia, limb
muscle weakness, and hyporeflexia. The patients also showed chronic
hemolytic anemia. Immunosuppressive treatment resulted in some clinical
improvement. Red blood cells derived from the patients showed lack of
CD59 expression, and sural nerve biopsy of 1 patient showed no CD59
expression. Western blot analysis detected reduced amounts of the
protein, suggesting that it is synthesized but fails to reach cell
membranes. Because C89Y disrupts a disulfide bond, the tertiary
structure of the mutant protein may be affected. Nevo et al. (2013)
suggested that improper activation of the complement system due to lack
of CD59 expression may cause damage to red cell membranes and result in
myelin and axonal damage.

ANIMAL MODEL

To examine the role of CD59 in protecting host tissues in health and
disease, Holt et al. (2001) generated Cd59-deficient (Cd59 -/-) mice by
gene targeting in embryonic stem cells. Despite the complete absence of
Cd59, mice were healthy and fertile. Red cells in vitro displayed
increased susceptibility to complement and were positive in an
acidified-serum lysis test. Despite this, Cd59 -/- mice were not anemic
but had elevated reticulocyte counts, indicating accelerated erythrocyte
turnover. Fresh plasma and urine from these mice contained increased
amounts of hemoglobin when compared with littermate controls, providing
further evidence for spontaneous intravascular hemolysis. Intravascular
hemolysis was increased following administration of cobra venom factor
to trigger complement activation.

*FIELD* AV
.0001
HEMOLYTIC ANEMIA, CD59-MEDIATED
CD59, 1-BP DEL, CODON 16

In a 23-year-old Japanese male with complete deficiency of CD59 (HACD59;
612300), Motoyama et al. (1992) identified single-nucleotide deletions
in codon 16 (GCC to GC) and codon 96 (GCA to CA). The homozygous
deletion in codon 16 resulted in a frameshift and introduced a stop
codon at position 54. The parents, who were cousins, were heterozygous
for the mutation. One sister was also heterozygous; a brother was
homozygous normal. Presumably it was the deletion in codon 16 that was
responsible for the effects on the protein resulting in CD59 deficiency.
The patient presented with paroxysmal nocturnal hemoglobinuria with
onset in adolescence. He had no involvement of the peripheral nervous
system at age 22 years (Nevo et al., 2013).

.0002
HEMOLYTIC ANEMIA, CD59-MEDIATED, WITH IMMUNE-MEDIATED POLYNEUROPATHY
CD59, CYS89TYR

In 5 patients from 4 unrelated families of North African Jewish descent
with CD59-mediated hemolytic anemia and immune-mediated polyneuropathy
(612300), Nevo et al. (2013) identified a homozygous c.266G-A transition
in exon 3 of the CD59 gene, resulting in a cys89-to-tyr (C89Y)
substitution at a highly conserved residue that participates in the
formation of a disulfide bond. The mutation was found by whole-exome
sequencing in 2 affected sibs, segregated with the disorder in all
families, and was not found in the dbSNP or the Exome Variant Server
database. Haplotype analysis indicated a founder effect, and the
mutation was found in heterozygous state in 3 of 197 ethnically matched
individuals (carrier rate of 1 in 66 in this community). Red blood cells
derived from the patients showed lack of CD59 expression, and sural
nerve biopsy of 1 patient showed no CD59 expression. Western blot
analysis detected reduced amounts of the protein, suggesting that it is
synthesized but fails to reach cell membranes. Because C89Y disrupts a
disulfide bond, the tertiary structure of the mutant protein may be
affected. Nevo et al. (2013) suggested that improper activation of the
complement system due to lack of CD59 expression may cause damage to red
cell membranes and result in myelin and axonal damage.

*FIELD* SA
Harada et al. (1990); Woodroofe et al. (1984)
*FIELD* RF
1. Acosta, J.; Hettinga, J.; Fluckiger, R.; Krumrei, N.; Goldfine,
A.; Angarita, L.; Halperin, J.: Molecular basis for a link between
complement and the vascular complications of diabetes. Proc. Nat.
Acad. Sci. 97: 5450-5455, 2000.

2. Bickmore, W. A.; Longbottom, D.; Oghene, K.; Fletcher, J. M.; van
Heyningen, V.: Colocalization of the human CD59 gene to 11p13 with
the MIC11 cell surface antigen. Genomics 17: 129-135, 1993.

3. Davies, A.; Simmons, D. L.; Hale, G.; Harrison, R. A.; Tighe, H.;
Lachmann, P. J.; Waldmann, H.: CD59, an LY-6-like protein expressed
in human lymphoid cells, regulates the action of the complement membrane
attack complex on homologous cells. J. Exp. Med. 170: 637-654, 1989.

4. Forsberg, U. H.; Bazil, V.; Stefanova, I.; Schroder, J.: Gene
for human CD59 (likely Ly-6 homologue) is located on the short arm
of chromosome 11. Immunogenetics 30: 188-193, 1989.

5. Gawin, B.; Niederfuhr, A.; Schumacher, N.; Hummerich, H.; Little,
P. F. R.; Gessler, M.: A 7.5 Mb sequence-ready PAC contig and gene
expression map of human chromosome 11p13-p14.1. Genome Res. 9: 1074-1086,
1999.

6. Harada, R.; Okada, N.; Fujita, T.; Okada, H.: Purification of
1F5 antigen that prevents complement attack on homologous cell membranes. J.
Immun. 144: 1823-1828, 1990.

7. Heckl-Ostreicher, B.; Ragg, S.; Drechsler, M.; Scherthan, H.; Royer-Pokora,
B.: Localization of the human CD59 gene by fluorescence in situ hybridization
and pulsed-field gel electrophoresis. Cytogenet. Cell Genet. 63:
144-146, 1993.

8. Holt, D. S.; Botto, M.; Bygrave, A. E.; Hanna, S. M.; Walport,
M. J.; Morgan, B. P.: Targeted deletion of the CD59 gene causes spontaneous
intravascular hemolysis and hemoglobinuria. Blood 98: 442-449, 2001.

9. Holt, D. S.; Powell, M. B.; Rushmere, N. K.; Morgan, B. P.: Genomic
structure and chromosome location of the gene encoding mouse CD59. Cytogenet.
Cell Genet. 89: 264-267, 2000.

10. Huppi, K.; Duncan, R.; Potter, M.: Myc-1 is centromeric to the
linkage group Ly-6-Sis-Gdc-1 on mouse chromosome 15. Immunogenetics 27:
215-219, 1988.

11. Kamiura, S.; Nolan, C. M.; Meruelo, D.: Long-range physical map
of the Ly-6 complex: mapping the Ly-6 multigene family by field-inversion
and two-dimensional gel electrophoresis. Genomics 12: 89-105, 1992.

12. Kumar, A.; Godwin, J. W.; Gates, P. B.; Garza-Garcia, A. A.; Brockes,
J. P.: Molecular basis for the nerve dependence of limb regeneration
in an adult vertebrate. Science 318: 772-777, 2007.

13. LeClair, K. P.; Rabin, M.; Nesbitt, M. N.; Pravtcheva, D.; Ruddle,
F. H.; Palfree, R. G. E.; Bothwell, A.: Murine Ly-6 multigene family
is located on chromosome 15. Proc. Nat. Acad. Sci. 84: 1638-1642,
1987.

14. Mao, M.; Yu, M.; Tong, J.-H.; Ye, J.; Zhu, J.; Huang, Q.-H.; Fu,
G.; Yu, L.; Zhao, S.-Y.; Waxman, S.; Lanotte, M.; Wang, Z.-Y.; Tan,
J.-Z.; Chan, S.-J.; Chen, Z.: RIG-E, a human homolog of the murine
Ly-6 family, is induced by retinoic acid during the differentiation
of acute promyelocytic leukemia cell. Proc. Nat. Acad. Sci. 93:
5910-5914, 1996.

15. Meri, S.; Morgan, B. P.; Davies, A.; Daniels, R. H.; Olavesen,
M. G.; Waldmann, H.; Lachmann, P. J.: Human protectin (CD59), an
18,000-20,000 MW complement lysis restricting factor, inhibits C5b-8
catalysed insertion of C9 into lipid bilayers. Immunology 71: 1-9,
1990.

16. Meri, S.; Morgan, B. P.; Wing, M.; Jones, J.; Davies, A.; Podack,
E.; Lachmann, P. J.: Human protectin (CD59), an 18-20-kD homologous
complement restriction factor, does not restrict perforin-mediated
lysis. J. Exp. Med. 172: 367-370, 1990.

17. Morais da Silva, S.; Gates, P. B.; Brockes, J. P.: The newt ortholog
of CD59 is implicated in proximodistal identity during amphibian limb
regeneration. Dev. Cell 3: 547-555, 2002.

18. Motoyama, N.; Okada, N.; Yamashina, M.; Okada, H.: Paroxysmal
nocturnal hemoglobinuria due to hereditary nucleotide deletion in
the HRF20 (CD59) gene. Europ. J. Immun. 22: 2669-2673, 1992.

19. Nevo, Y.; Ben-Zeev, B.; Tabib, A.; Straussberg, R.; Anikster,
Y.; Shorer, Z.; Fattal-Valevski, A.; Ta-Shma, A.; Aharoni, S.; Rabie,
M.; Zenvirt, S.; Goldshmidt, H.; Fellig, Y.; Shaag, A.; Mevorach,
D.; Elpeleg, O.: CD59 deficiency is associated with chronic hemolysis
and childhood relapsing immune-mediated polyneuropathy. Blood 121:
129-135, 2013.

20. Okada, N.; Harada, R.; Fujiita, T.; Okada, H.: A novel membrane
glycoprotein capable of inhibiting membrane attack by homologous complement. Int.
Immun. 1: 205-208, 1989.

21. Petranka, J. G.; Fleenor, D. E.; Sykes, K.; Kaufman, R. E.; Rosse,
W. F.: Structure of the CD59-encoding gene: further evidence of a
relationship to murine lymphocyte antigen Ly-6 protein. Proc. Nat.
Acad. Sci. 89: 7876-7879, 1992. Note: Erratum: Proc. Nat. Acad. Sci.
90: 5878 only, 1993.

22. Rother, R. P.; Rollins, S. A.; Mennone, J.; Chodera, A.; Fidel,
S. A.; Bessler, M.; Hillmen, P.; Squinto, S. P.: Expression of recombinant
transmembrane CD59 in paroxysmal nocturnal hemoglobinuria B cells
confers resistance to human complement. Blood 84: 2604-2611, 1994.

23. Sood, R.; Zehnder, J. L.; Druzin, M. L.; Brown, P. O.: Gene expression
patterns in human placenta. Proc. Nat. Acad. Sci. 103: 5478-5483,
2006.

24. Tone, M.; Walsh, L. A.; Waldmann, H.: Gene structure of human
CD59 and demonstration that discrete mRNAs are generated by alternative
polyadenylation. J. Molec. Biol. 227: 971-976, 1992.

25. Walsh, L. A.; Tone, M.; Thiru, S.; Waldmann, H.: The CD59 antigen--a
multifunctional molecule. Tissue Antigens 40: 213-220, 1992.

26. Woodroofe, M. N.; Tunnacliffe, A.; Pym, B.; Goodfellow, P. N.;
Walsh, F. S.: Human muscle cell surface antigen 16-3A5 is encoded
by a gene on chromosome 11. Somat. Cell Molec. Genet. 10: 535-540,
1984.

*FIELD* CN
Cassandra L. Kniffin - updated: 9/12/2013
Patricia A. Hartz - updated: 9/16/2008
Patricia A. Hartz - updated: 12/3/2007
Ada Hamosh - updated: 11/21/2007
Anne M. Stumpf - updated: 8/8/2006
Ada Hamosh - updated: 8/8/2006
Victor A. McKusick - updated: 10/9/2001
Carol A. Bocchini - updated: 1/16/2001
Victor A. McKusick - updated: 7/21/2000

*FIELD* CD
Victor A. McKusick: 12/12/1989

*FIELD* ED
carol: 09/16/2013
carol: 9/16/2013
carol: 9/13/2013
ckniffin: 9/12/2013
carol: 3/21/2013
mgross: 7/1/2010
mgross: 9/17/2008
terry: 9/16/2008
mgross: 12/4/2007
terry: 12/3/2007
alopez: 11/28/2007
terry: 11/21/2007
wwang: 3/2/2007
alopez: 8/8/2006
mgross: 3/17/2004
ckniffin: 8/26/2002
carol: 11/13/2001
mcapotos: 10/19/2001
terry: 10/9/2001
carol: 1/16/2001
alopez: 7/25/2000
terry: 7/21/2000
carol: 3/6/2000
dkim: 12/16/1998
mark: 9/1/1997
terry: 8/21/1996
terry: 7/16/1996
mark: 7/8/1996
carol: 1/24/1995
warfield: 4/7/1994
carol: 7/13/1993
carol: 7/6/1993
carol: 6/9/1993
carol: 6/8/1993

MIM 612300
*RECORD*
*FIELD* NO
612300
*FIELD* TI
#612300 HEMOLYTIC ANEMIA, CD59-MEDIATED, WITH OR WITHOUT IMMUNE-MEDIATED POLYNEUROPATHY;
read moreHACD59
;;CD59 DEFICIENCY
*FIELD* TX
A number sign (#) is used with this entry because CD59-mediated
hemolytic anemia with or without immune-mediated polyneuropathy is
caused by homozygous mutation in the CD59 gene (107271) on chromosome
11p13.

DESCRIPTION

CD59-mediated hemolytic anemia with immune-mediated polyneuropathy is an
autosomal recessive disorder characterized by infantile onset of a
relapsing-remitting polyneuropathy, often exacerbated by infection, and
manifest as hypotonia, limb muscle weakness, and hyporeflexia.
Immunosuppressive treatment may result in some clinical improvement
(summary by Nevo et al., 2013).

CLINICAL FEATURES

Yamashina et al. (1990) found that the erythrocytes from a patient
thought to have paroxysmal nocturnal hemoglobinuria (PNH; 300818) were
devoid of HRF20 (CD59) and that those of his parents were deficient in
the protein, compatible with the heterozygous state. The patient,
previously described by Ono et al. (1990), was a 22-year-old man with
intermittent pallor and hematuria of 9 years' duration. Paroxysmal
nocturnal hemoglobinuria had been diagnosed at the age of 13 years when
he had an episode of hemolytic anemia and hemoglobinuria. During the
subsequent 9 years, Ham and sucrose hemolysis tests were consistently
positive, and 9 episodes of hemolysis occurred, with a cerebral
infarction during the third and ninth episodes. His father and mother
were cousins, but neither had a history of hemolytic anemia or
hemoglobinuria. Rosse (1993) pointed out that although the patient had
hemolytic anemia and thrombosis typical of PNH, he did not have other
features of PNH, which is due to deficiency of PIGA (311770), the
molecule that anchors CD59 and several other molecules to the cell
surface. Nevo et al. (2013) noted that the patient reported by Yamashina
et al. (1990) was not reported to have evidence of polyneuropathy.

Nevo et al. (2013) reported 5 children from 4 unrelated families of
North African Jewish descent who presented with infantile onset of
relapsing immune-mediated polyneuropathy and chronic hemolysis. One of
the families was consanguineous. Disease onset was between age 3 and 7
months and was usually preceded by a minor viral illness. Symptoms
included symmetric muscle weakness, hypotonia, and hyporeflexia
affecting the lower limbs more than the upper limbs. The first episode
lasted from days to weeks and treatment with IV immunoglobulins and
corticosteroids resulted in restoration of muscle strength in the upper
extremities. However, the disease course was relapsing-remitting in the
following months, with exacerbations after infections. There was
progressive muscle atrophy of the hands and feet, and persistent
paralysis of the lower limbs associated with areflexia. A few of the
exacerbations were accompanied by respiratory insufficiency requiring
artificial ventilation, and 1 patient developed an acute episode of
hemolytic-uremic syndrome during plasmapheresis that resolved. Cognitive
development was normal. Laboratory studies during episodes showed acute
hemolysis with decreased hemoglobin, increased C-reactive protein, and
increased CSF protein levels. Nerve conduction studies showed
demyelination with axonal damage in 2 of 3 patients, and spinal MRI
showed root enhancement in 2 of 3 patients. Magnetic resonance imaging
of the spine performed in 3 patients revealed root enhancement in 2
patients. Immunosuppressive treatment improved the time between relapses
and reduced severity, but did not prevent recurrence. One patient died
of acute respiratory failure at age 3.5 years.

INHERITANCE

The transmission pattern in the family with chronic hemolysis and
immune-mediated polyneuropathy reported by Nevo et al. (2013) was
consistent with autosomal recessive inheritance.

MAPPING

CD59 deficiency is caused by mutation in the CD59 gene, which maps to
chromosome 11p13 (Heckl-Ostreicher et al., 1993).

MOLECULAR GENETICS

Motoyama et al. (1992) identified a homozygous single-nucleotide
deletion in the CD59 gene (107271.0001) in the patient with CD59
deficiency and hemolytic anemia reported by Yamashina et al. (1990) and
Ono et al. (1990).

In 5 patients from 4 unrelated families of North African Jewish descent
with CD59-mediated hemolytic anemia and immune-mediated polyneuropathy,
Nevo et al. (2013) identified a homozygous mutation in the CD59 gene
(C89Y; 107271.0002). The mutation was initially found by whole-exome
sequencing in 2 affected sibs, segregated with the disorder in all
families, and was not found in the dbSNP and the Exome Variant Server
databases. Haplotype analysis indicated a founder effect. Nevo et al.
(2013) suggested that improper activation of the complement system due
to lack of CD59 expression may cause damage to red cell membranes and
result in myelin and axonal damage.

ANIMAL MODEL

To examine the role of CD59 in protecting host tissues in health and
disease, Holt et al. (2001) generated Cd59-deficient (Cd59 -/-) mice by
gene targeting in embryonic stem cells. Despite the complete absence of
Cd59, mice were healthy and fertile. Red cells in vitro displayed
increased susceptibility to complement and were positive in an
acidified-serum lysis test. Despite this, Cd59 -/- mice were not anemic
but had elevated reticulocyte counts, indicating accelerated erythrocyte
turnover. Fresh plasma and urine from these mice contained increased
amounts of hemoglobin when compared with littermate controls, providing
further evidence for spontaneous intravascular hemolysis. Intravascular
hemolysis was increased following administration of cobra venom factor
to trigger complement activation.

*FIELD* RF
1. Heckl-Ostreicher, B.; Ragg, S.; Drechsler, M.; Scherthan, H.; Royer-Pokora,
B.: Localization of the human CD59 gene by fluorescence in situ hybridization
and pulsed-field gel electrophoresis. Cytogenet. Cell Genet. 63:
144-146, 1993.

2. Holt, D. S.; Botto, M.; Bygrave, A. E.; Hanna, S. M.; Walport,
M. J.; Morgan, B. P.: Targeted deletion of the CD59 gene causes spontaneous
intravascular hemolysis and hemoglobinuria. Blood 98: 442-449, 2001.

3. Motoyama, N.; Okada, N.; Yamashina, M.; Okada, H.: Paroxysmal
nocturnal hemoglobinuria due to hereditary nucleotide deletion in
the HRF20 (CD59) gene. Europ. J. Immun. 22: 2669-2673, 1992.

4. Nevo, Y.; Ben-Zeev, B.; Tabib, A.; Straussberg, R.; Anikster, Y.;
Shorer, Z.; Fattal-Valevski, A.; Ta-Shma, A.; Aharoni, S.; Rabie,
M.; Zenvirt, S.; Goldshmidt, H.; Fellig, Y.; Shaag, A.; Mevorach,
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5. Ono, H.; Kuno, Y.; Tanaka, H.; Yamashina, M.; Tsuyoshi, T.; Kondo,
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6. Rosse, W. F.: Personal Communication. Durham, N. C. 6/3/1993.

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Eng. J. Med. 323: 1184-1189, 1990.

*FIELD* CS
INHERITANCE:
Autosomal recessive

MUSCLE, SOFT TISSUE:
Hypotonia;
Muscle weakness, upper and lower limbs;
Muscle atrophy, progressive;
Hand and foot weakness

NEUROLOGIC:
[Peripheral nervous system];
Chronic immune-mediated polyneuropathy;
Limb weakness;
Limb paralysis;
Areflexia;
Sensory and motor demyelination seen on sural nerve biopsy;
Secondary axonal damage

HEMATOLOGY:
Hemolytic anemia

LABORATORY ABNORMALITIES:
Increased CSF protein;
Absence of CD59 expression on red cells

MISCELLANEOUS:
Onset in infancy (3 to 7 months);
Exacerbations during infection;
Relapsing-remitting course;
Immunosuppressive therapy may be beneficial

MOLECULAR BASIS:
Caused by mutation in the CD59 antigen gene (CD59, 107271.0001)

*FIELD* CD
Cassandra L. Kniffin: 9/11/2013

*FIELD* ED
joanna: 09/24/2013
ckniffin: 9/12/2013

*FIELD* CN
Cassandra L. Kniffin - updated: 9/12/2013

*FIELD* CD
Matthew B. Gross: 9/17/2008

*FIELD* ED
carol: 09/16/2013
carol: 9/16/2013
carol: 9/13/2013
ckniffin: 9/12/2013
mgross: 7/1/2010
mgross: 9/17/2008